An abnormality in myocardial energy metabolism occurs in hearts of untreated diabetic rats when treated with physiological or elevated concentrations of fatty acids. A decrease in ATP levels associated with a carnitine deficiency and elevated fatty acyl coenzyme A is observed with no change in phosphocreatine levels. Evidence suggests that this abnormality in high energy phosphate metabolism may be responsible for the increased susceptibility of diabetics to sudden death, coronary heart disease, congestive heart failure and other cardiovascular problems. A long-range objective of our laboratory is to explore the effects that therapeutic agents used in diabetic patients may exert on high- energy phosphate metabolism. As a first step to meet this objective, we wish to examine tolbutamide, an oral hypoglycemic agent whose use in diabetic patients is associated with an increased mortality from cardiovascular causes that has not been satisfactorily explained. This study will test the hypothesis that tolbutamide exaggerates the abnormality in myocardial energy metabolism. Control and diabetic rat hearts will be perfused for 1 hr with medium both with and without a fatty acid/albumin complex. Following this control period, perfusion during the second and third hours will incorporate concentrations of tolbutamide corresponding to serum therapeutic levels to determine its effect. Non-destructive, sequential analysis of myocardial high-energy phosphates will be provided by phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy. After perfusion, hearts will be frozen in liquid nitrogen for HPLC analyses of total adenine nucleotide pool and concentrations of fatty acyl coenzyme A, carnitine and acylcarnitines. Supplementation of the perfusion media with L-carnitine will be evaluated as a means to attenuate abnormal energy metabolism. Results from these studies may provide experimental evidence for a possible explanation of the increased mortality associated with the therapeutic use of oral hypoglycemic agents and provide a rational means to prevent the effect. Moreover, it will provide an opportunity to develop an experimental protocol with which to investigate the effect on myocardial energy metabolism of other agents commonly used by diabetic patients.